Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof

ABSTRACT

Biocompatible intraocular implants include an alpha-2 adrenergic receptor agonist and a polymer associated with the alpha-2 adrenergic receptor agonist to facilitate release of the alpha-2 adrenergic receptor agonist into an eye for an extended period of time. The alpha-2 adrenergic receptor agonist may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. The implants can be placed in an eye to treat one or more ocular conditions, such as an ocular vasculopathy or glaucoma, including reduction of an elevated intraocular pressure.

CROSS-REFERENCE

This application is a continuation of copending U.S. patent applicationSer. No. 15/864,990, filed on Jan. 8, 2018, which is a continuation ofU.S. patent application Ser. No. 15/383,079, filed on Dec. 19, 2016,which is a continuation of U.S. patent application Ser. No. 14/816,401,filed on Aug. 3, 2015, now issued as U.S. Pat. No. 9,522,113, which is acontinuation of U.S. patent application Ser. No. 12/272,548, filed onNov. 17, 2008, now issued as U.S. Pat. No. 9,095,506, all of which areincorporated by reference herein in their entirety.

BACKGROUND

The present invention relates to bioerodible, sustained releaseintraocular implants and methods for treating an ocular disease orcondition. Brimonidine(5-bromo-6-(2-imidazolidinylideneamino)quinoxaline) is analpha-2-selective adrenergic receptor agonist effective for treatingopen-angle glaucoma by decreasing aqueous humor production andincreasing uveoscleral outflow. Brimonidine is available in at least twochemical forms, brimonidine tartrate and brimonidine free base. Topicalocular brimonidine tartrate formulation, 0.15% Alphagan P® (Allergan,Irvine, Calif.), has been used to treat of open-angle glaucoma. Thesolubility of brimonidine tartrate in water is 34 mg/mL, while thesolubility of brimonidine freebase is negligible in water. Topicalformulations of brimonidine to treat glaucoma are administered daily.Hence, it would be advantageous to have a sustained release formulationof an alpha-2-selective adrenergic receptor agonist, such asbrimonidine, which can be administered (i.e. by intrascleral injectionor implantation of a suitable implant) once every one to six months toprovide regular dosing of the alpha-2-selective adrenergic receptoragonist therapeutic agent to the eye of a patient in need thereof tothereby treat an ocular condition such as the elevated intraocularpressure characteristic of glaucoma.

Recent studies have suggested that brimonidine can also promote survivalof injured retinal ganglion nerve cells by activation of thealpha-2-adrenoceptor in the retina and/or optic nerve. For example,brimonidine can protect injured neurons from further damage in severalmodels of ischemia and glaucoma. See e.g. U.S. Pat. Nos. 5,856,329;6,194,415; 6,248,741, and; 6,465,464.

Glaucoma-induced retinal ganglion cell degeneration (neurodegeneration)is one of the leading causes of blindness. This indicates thatbrimonidine can be utilized in glaucoma management in whichneuroprotection (through mitigation of neurodegeneration) and/orintraocular pressure reduction are valued outcomes of the therapeuticregimen. For brimonidine to protect the optic nerve, however, it musthave access to the posterior segment of the eye at therapeutic levels.Hence, it would be advantageous to have a sustained release formulationof an alpha-2-selective adrenergic receptor agonist, such asbrimonidine, which can be administered (i.e. by intravitreal injectionor implantation of a suitable implant) once every one to six months toprovide regular dosing of the alpha-2-selective adrenergic receptoragonist therapeutic agent to the eye of a patient in need thereof tothereby treat an ocular condition such as neurodegeneration anotherretinal disorder or condition such as macular degeneration, macularedema or other retinopathy.

Macular degeneration, such as age related macular degeneration (“AMD”)is a leading cause of blindness in the world. It is estimated thatthirteen million Americans have evidence of macular degeneration.Macular degeneration results in a break down the macula, thelight-sensitive part of the retina responsible for the sharp, directvision needed to read or drive. Central vision is especially affected.Macular degeneration is diagnosed as either dry (atrophic) or wet(exudative). The dry form of macular degeneration is more common thanthe wet form of macular degeneration, with about 90% of AMD patientsbeing diagnosed with dry AMD. The wet form of the disease usually leadsto more serious vision loss. Macular degeneration can produce a slow orsudden painless loss of vision. The cause of macular degeneration is notclear. The dry form of AMD may result from the aging and thinning ofmacular tissues, depositing of pigment in the macula, or a combinationof the two processes. With wet AMD, new blood vessels grow beneath theretina and leak blood and fluid. This leakage causes retinal cells todie and creates blind spots in central vision.

Macular edema (“ME”) can result in a swelling of the macula. The edemais caused by fluid leaking from retinal blood vessels. Blood leaks outof the weak vessel walls into a very small area of the macula which isrich in cones, the nerve endings that detect color and from whichdaytime vision depends. Blurring then occurs in the middle or just tothe side of the central visual field. Visual loss can progress over aperiod of months. Retinal blood vessel obstruction, eye inflammation,and age-related macular degeneration have all been associated withmacular edema. The macula may also be affected by swelling followingcataract extraction. Symptoms of ME include blurred central vision,distorted vision, vision tinted pink and light sensitivity. Causes of MEcan include retinal vein occlusion, macular degeneration, diabeticmacular leakage, eye inflammation, idiopathic central serouschorioretinopathy, anterior or posterior uveitis, pars planitis,retinitis pigmentosa, radiation retinopathy, posterior vitreousdetachment, epiretinal membrane formation, idiopathic juxtafovealretinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patientswith ME may have a history of use of topical epinephrine orprostaglandin analogs for glaucoma. The first line of treatment for MEis typically anti-inflammatory drops topically applied.

Diabetic retinopathy is the leading cause of blindness among adults aged20 to 74 years. Macular ischemia is a major cause of irreversible visionacuity loss and decreased contrast sensitivity in patients with diabeticretinopathy. The capillary nonperfusion and decreased capillary bloodflow that is responsible for this ischemia is seen clinically on thefluorescein angiogram as an increase in the foveal avascular zone (FAZ)or an irregularity of the outline of the FAZ. These findings arepredictors of the other, perhaps more well-known, sight-threateningcomplications of diabetic retinopathy, including macular edema andproliferative retinopathy. Perhaps more importantly, extensive capillarynonperfusion is also a predictor of a poor visual prognosis fromdiabetic retinopathy.

The exterior surface of the normal globe mammalian eye has a layer oftissue known as conjunctival epithelium, under which is a layer oftissue called Tenon's fascia (also called conjunctival stroma). Theextent of the Tenon's fascia extending backwards across the globe formsa fascial sheath known as Tenon's capsule. Under Tenon's fascia is theepisclera. Collectively, the conjunctival epithelium and the Tenon'sfascia is referred to as the conjunctiva. As noted, under Tenon's fasciais the episclera, underneath which lies the sclera, followed by thechoroid. Most of the lymphatic vessels and their associated drainagesystem, which is very efficient at removing therapeutic agents placed intheir vicinity, is present in the conjunctiva of the eye.

A therapeutic agent can be administered to the eye to treat an ocularcondition. For example the target tissue for an antihypertensivetherapeutic agent to treat the elevated intraocular pressurecharacteristic of glaucoma can be the ciliary body and/or the trabecularmeshwork. Unfortunately, administration of an ocular topicalantihypertensive pharmaceutical in the form of eye drops can result in arapid wash out of most if not all of the therapeutic agent before itreaches the ciliary body and/or the trabecular meshwork target tissue,thereby requiring frequent redosing to effectively treat a hypertensivecondition. Additionally, side effects to patients from topicaladministration of antiglaucoma medications and their preservatives rangefrom ocular discomfort to sight-threatening alterations of the ocularsurface, including conjunctival hyperemia (eye redness), stinging, pain,decreased tear production and function, decreased tear film stability,superficial punctate keratitis, squamous cell metaplasia, and changes incell morphology. These adverse effects of topical antiglaucoma eyedropscan interfere with the treatment of glaucoma by discouraging patientdosing compliance, and as well long-term treatment with eyedrops isassociated with a higher failure of filtration surgery. Asbell P. A., etal Effects of topical antiglaucoma medications on the ocular surface,Ocul Surf 2005 January; 3(1):27-40; Mueller M., et al. Tear film breakup time and Schirmer test after different antiglaucomatous medications,Invest Ophthalmol Vis Sci 2000 Mar. 15; 41(4):5283. Thus it would beadvantageous to have an intraocular, sustained release formulation of analpha-2 agonist for treating glaucoma which does not have the sideeffects rapid drug wash out, ocular discomfort, conjunctival hyperemia(eye redness), stinging, pain, decreased tear production and function,decreased tear film stability, superficial punctate keratitis, squamouscell metaplasia, and changes in cell morphology.

It is known to administer a drug depot to the posterior (i.e. near themacula) sub-Tenon space. See eg column 4 of U.S. Pat. No. 6,413,245.Additionally, it is known to administer a polylactic implant to thesub-tenon space or to a suprachoroidal location. See eg published U.S.Pat. No. 5,264,188 and published U.S. patent application 20050244463.

Drug delivery systems have been formulated with various active agents.For example, it is known to make 2-methoxyestradiol poly lactic acidpolymer implants (as rods and wafers), intended for intraocular use, bya melt extrusion method. See eg published U.S. patent application20050244471. Additionally, it is known to make brimonidine poly lacticacid polymer implants and microspheres intended for intraocular use. Seeeg published U.S. patent applications 20050244463 and 20050244506, andU.S. patent application Ser. No. 11/395,019. Furthermore, it is known tomake bimatoprost containing polylactic acid polymer implants andmicrospheres intended for intraocular use. See eg published U.S. patentapplications 2005 0244464 and 2006 0182781, and U.S. patent applicationsSer. Nos. 11/303,462, and; 11/371,118.

Brimonidine is an α_(2B)-selective adrenergic agonist used to treatopen-angle glaucoma by decreasing aqueous humor production andincreasing uveoscleral outflow. The chemical structure of brimonidinetartrate is:

The chemical formula for brimonidine tartrate is F,5-bromo-6-(2-imidazolidinylideneamino)quinoxaline tartrate C₁₅H₁₆N₅O₆Bror (C₁₁H₁₀BrN5.C₄H₆O₆).

Brimonidine tartrate has been used in ophthalmic solutions inconcentrations of 0.2%, 0.15% and 0.1%. It has been suggested thatbrimonidine can have a neuroprotective effect upon retinal cells. See egU.S. Pat. Nos. 5,856,329; 6,194,415; 6,248,741, and; 6,465,464.

Biocompatible implants for placement in the eye have been disclosed in anumber of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224;4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072;5,869,079; 6,074,661; 6,331,313; 6,369,116; 6,066,675, and 6,699,493.Relevant U.S. patent application Ser. Nos. 10/020,541; 09/998,718;10/836,911; 11/119,021; 11/394,765; 12/024,010; 12/024,014; 12/024,017;10/837,143; 11/118,519; 11/927,613; 11/927,615; 11/395,019, and11/565,917.

It would be advantageous to provide eye implantable drug deliverysystems, such as intraocular implants, and methods of using suchsystems, that are capable of releasing a therapeutic agent at asustained or controlled rate for extended periods of time and in amountswith few or no negative side effects to treat an ocular disease orcondition such as glaucoma, neurodegeneration, or a retinal disorder orcondition.

SUMMARY

The present invention meets this need and provides new drug deliverysystems, and methods of making and using such systems for extended orsustained drug release into an eye to treat an ocular disease orcondition. Our drug delivery systems are in the form of intraocularimplants. The present systems and methods advantageously provide forextended release times of one or more therapeutic agents. Thus, thepatient in whose eye the implant has been placed receives a therapeuticamount of an agent for a long or extended time period without requiringadditional administrations of the agent. Thus, the patient has asubstantially consistent level of therapeutically active agent availablefor consistent treatment of the eye over a relatively long period oftime, for example, on the order of at least about one week, such asbetween about two and about six months after receiving an implant. Suchextended release times facilitate obtaining successful treatmentresults.

Definitions

As use herein the terms below have the meanings set forth.

“About” means plus or minus ten percent of the value, parameter orcharacteristic so qualified.

“Biocompatible” means that there is an insignificant inflammatoryresponse upon contact of the biocompatible material with an oculartissue.

“Effective amount” as applied to an active agent means that amount ofthe compound which is generally sufficient to effect a desired change inthe subject.

“Intraocular implant” means a device or element that is structured,sized, or otherwise configured to be placed in an eye. Intraocularimplants are generally biocompatible with physiological conditions of aneye and do not cause adverse side effects. Intraocular implants may beplaced in an eye without disrupting vision of the eye.

“Therapeutic component” means a portion of an intraocular implantcomprising one or more therapeutic agents or substances used to treat amedical condition of the eye. The therapeutic component may be adiscrete region of an intraocular implant, or it may be homogenouslydistributed throughout the implant. The therapeutic agents of thetherapeutic component are typically ophthalmically acceptable, and areprovided in a form that does not cause adverse reactions when theimplant is placed in an eye.

“Drug release sustaining component” means a portion of the intraocularimplant that is effective to provide a sustained release of thetherapeutic agents of the implant. A drug release sustaining componentmay be a biodegradable polymer matrix, or it may be a coating covering acore region of the implant that comprises a therapeutic component.

“Associated with” means mixed with, dispersed within, coupled to,covering, or surrounding.

“Ocular region” or “ocular site” means any area of the eyeball,including the anterior and posterior segment of the eye, and whichgenerally includes, but is not limited to, any functional (e.g., forvision) or structural tissues found in the eyeball, or tissues orcellular layers that partly or completely line the interior or exteriorof the eyeball. Specific examples of areas of the eyeball in an ocularregion include the anterior chamber, the posterior chamber, the vitreouscavity, the choroid, the suprachoroidal space, the conjunctiva, thesubconjunctival space, the episcleral space, the intracorneal space, theepicorneal space, the sclera, the pars plana, surgically-inducedavascular regions, the macula, and the retina.

“Ocular condition” means a disease, ailment or condition which affectsor involves the eye or one of the parts or regions of the eye. Broadlyspeaking the eye includes the eyeball and the tissues and fluids whichconstitute the eyeball, the periocular muscles (such as the oblique andrectus muscles) and the portion of the optic nerve which is within oradjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic ophthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

“Biodegradable polymer” means a polymer or polymers which degrade invivo, and wherein erosion of the polymer or polymers over time occursconcurrent with or subsequent to release of the therapeutic agent.Specifically, hydrogels such as methylcellulose which act to releasedrug through polymer swelling are specifically excluded from the term“biodegradable polymer”. The terms “biodegradable” and “bioerodible” areequivalent and are used interchangeably herein. A biodegradable polymermay be a homopolymer, a copolymer, or a polymer comprising more than twodifferent polymeric units.

“Treat”, “treating”, or “treatment” means a reduction or resolution orprevention of an ocular condition, ocular injury or damage, or topromote healing of injured or damaged ocular tissue.

“Therapeutically effective amount” means the level or amount of agentneeded to treat an ocular condition, or reduce or prevent ocular injuryor damage without causing significant negative or adverse side effectsto the eye or a region of the eye.

Intraocular implants in accordance with the disclosure herein comprise atherapeutic component and a drug release sustaining component associatedwith the therapeutic component. In accordance with the presentinvention, the therapeutic component comprises, consists essentially of,or consists of, an alpha-2 adrenergic receptor agonist. The alpha-2adrenergic receptor agonist may be an agonist or agent that selectivelyactivates alpha-2 adrenergic receptors, for example by binding to analpha-2 adrenergic receptor, relative to other types of adrenergicreceptors, such as alpha-1 adrenergic receptors. The selectiveactivation can be achieved under different conditions, but preferably,the selective activation is determined under physiological conditions,such as conditions associated with an eye of a human or animal patient.The drug release sustaining component is associated with the therapeuticcomponent to sustain release of an amount of the alpha-2 adrenergicreceptor agonist into an eye in which the implant is placed. The amountof the alpha-2 adrenergic receptor agonist is released into the eye fora period of time greater than about one week after the implant is placedin the eye and is effective in preventing, reducing or treating anocular disease or condition such as glaucoma, neurodegeneration, aretinal disorder or condition or an ocular vasculopathy, such asvascular occlusion.

In one embodiment, the intraocular implants comprise an alpha-2adrenergic receptor agonist and a biodegradable polymer matrix. Thealpha-2 adrenergic receptor agonist is associated with a biodegradablepolymer matrix that degrades at a rate effective to sustain release ofan amount of the agonist from the implant for a time sufficient toreduce or prevent an ocular vascular occlusion. The intraocular implantis biodegradable or bioerodible and provides a sustained release of thealpha-2 adrenergic receptor agonist in an eye for extended periods oftime, such as for more than one week, for example for about three monthsor more and up to about six months or more. In certain implants, thealpha-2 adrenergic receptor agonist is released for about 30-35 days orless. In other implants, the alpha-2 adrenergic receptor agonist isreleased for 40 days or more.

The biodegradable polymer component of the foregoing implants may be amixture of biodegradable polymers, wherein at least one of thebiodegradable polymers is a polylactic acid polymer having a molecularweight less than 64 kiloDaltons (kD). Additionally or alternatively, theforegoing implants may comprise a first biodegradable polymer of apolylactic acid, and a different second biodegradable polymer of apolylactic acid. Furthermore, the foregoing implants may comprise amixture of different biodegradable polymers, each biodegradable polymerhaving an inherent viscosity in a range from about 0.2 (or about 0.3)deciliters/gram (dl/g) to about 1.0 dl/g.

The alpha-2 adrenergic receptor agonist of the implants disclosed hereinmay include quinoxaline derivatives, or other agonists that areeffective in treating ocular conditions. One example of a suitablequinoxaline derivative is brimonidine or brimonidine tartrate. Inaddition, the therapeutic component of the present implants may includeone or more additional and different therapeutic agents that may beeffective in treating an ocular condition.

A method of making the present implants involves combining or mixing thealpha-2 adrenergic receptor agonist with a biodegradable polymer orpolymers. The mixture may then be extruded or compressed to form asingle composition. The single composition may then be processed to formindividual implants suitable for placement in an eye of a patient.

The implants may be placed in an ocular region to treat a variety ofocular conditions, including conditions such as ocular vasculopathiesthat affect an anterior region or posterior region of an eye. Forexample, the implants may be used to treat many conditions of the eye,including, without limitation, conditions associated with vascularocclusion.

Kits in accordance with the present invention may comprise one or moreof the present implants, and instructions for using the implants. Forexample, the instructions may explain how to administer the implants toa patient, and types of conditions that may be treated with theimplants.

The present invention also encompasses a biodegradable intraocularimplant for improving vision. The implant can comprise an alpha-2adrenergic receptor agonist and a biodegradable polymer. The implantreleases the alpha-2 adrenergic receptor agonist from the polymer, uponintravitreal placement of the implant, in an amount effective to improvethe vision of the eye in which the implant is placed. The alpha-2adrenergic receptor agonist can be a quinoxaline, such as a(2-imidazolin-2-ylamino)quinoxaline, a5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline, and derivatives thereofand mixtures thereof. Thus, the alpha-2 adrenergic receptor agonist canbe a brimonidine or salts thereof or mixtures thereof. For example, thealpha-2 adrenergic receptor agonist can be brimonidine tartrate.

The alpha-2 adrenergic receptor agonist can be dispersed within thebiodegradable polymer of the implant. The biodegradable polymer cancomprise a mixture of a first biodegradable polymer of polylactic acid,and a different second biodegradable polymer of polylactic acid. Thepolymer can release drug at a rate effective to sustain release of anamount of the alpha-2 adrenergic receptor agonist from the implant formore than one month or for more that forty days or for less than thirtyfive days from the time the implant is placed in the vitreous of theeye.

An embodiment of the present invention is a method of making abiodegradable intraocular implant by extruding a mixture of an alpha-2adrenergic receptor agonist and a biodegradable polymer component toform a biodegradable material that releases drug at a rate effective tosustain release of an amount of the alpha-2 adrenergic receptor agonistfrom the implant for a time effective to improve vision in an eye inwhich the implant is placed.

A further embodiment of the present invention is a method for improvingor for maintaining vision by placing in the vitreous of an eye abiodegradable intraocular implant comprising an alpha-2 adrenergicreceptor agonist associated with a biodegradable polymer, therebyimproving or maintaining vision. This method can be used to treat anocular condition such as: macular degeneration, macular edema, retinalarterial occlusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, hemi-retinal vein occlusion, central retinal arteryocclusion, branch retinal artery occlusion, carotid artery disease(cad), eales disease, vasculopathies associated with diabetes,Non-Exudative Age Related Macular Degeneration, Exudative Age RelatedMacular Degeneration, Choroidal Neovascularization, DiabeticRetinopathy, Acute Macular Neuroretinopathy, Central SerousChorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, AcuteMultifocal Placoid Pigment Epitheliopathy, Behcet's Disease, BirdshotRetinochoroidopathy, Syphilis, Lyme, Tuberculosis, Toxoplasmosis,Intermediate Uveitis, Multifocal Choroiditis, Multiple Evanescent WhiteDot Syndrome, Ocular Sarcoidosis, Posterior Scleritis, SerpiginousChoroiditis, Subretinal Fibrosis and Uveitis Syndrome,Vogt-Koyanagi-Harada Syndrome, Coat's Disease, ParafovealTelangiectasia, Papillophlebitis, Frosted Branch Angiitis, Sickle CellRetinopathy and other Hemoglobinopathies, Angioid Streaks, FamilialExudative Vitreoretinopathy, Sympathetic Ophthalmia, Uveitic RetinalDisease, Retinal Detachment, Trauma, Laser, photodynamic therapy,Photocoagulation, Hypoperfusion During Surgery, Radiation Retinopathy,Bone Marrow Transplant Retinopathy, Proliferative Vitreal Retinopathyand Epiretinal Membranes, Proliferative Diabetic Retinopathy, OcularHistoplasmosis, Ocular Toxocariasis, Presumed Ocular HistoplasmosisSyndrome, Endophthalmitis, Toxoplasmosis, Retinal Diseases Associatedwith HIV Infection, Choroidal Disease Associated with HIV Infection,Uveitic Disease Associated with HIV Infection, Viral Retinitis, AcuteRetinal Necrosis, Progressive Outer Retinal Necrosis, Fungal RetinalDiseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse UnilateralSubacute Neuroretinitis, Myiasis, Retinitis Pigmentosa, SystemicDisorders with Associated Retinal Dystrophies, Congenital StationaryNight Blindness, Cone Dystrophies, Stargardt's Disease and FundusFlavimaculatus, Best's Disease, Pattern Dystrophy of the RetinalPigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy,Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy,pseudoxanthoma elasticum, Retinal Detachment, Macular Hole, GiantRetinal Tear, Retinal Disease Associated with Tumors, CongenitalHypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma,Choroidal Osteoma, Choroidal Metastasis, Combined Hamartoma of theRetina and Retinal Pigmented Epithelium, Retinoblastoma,Vasoproliferative Tumors of the Ocular Fundus, Retinal Astrocytoma,Intraocular Lymphoid Tumors, Punctate Inner Choroidopathy, AcutePosterior Multifocal Placoid Pigment Epitheliopathy, Myopic RetinalDegeneration, and Acute Retinal Pigment Epithelitis.

The implant can release the alpha-2 adrenergic receptor agonist from thepolymer, upon intravitreal placement of the implant, for a period ofabout ninety days. Significantly, the alpha-2 adrenergic receptoragonist can be retained in the retina for a period of time longer thanit is retained in the vitreous. An embodiment of the present inventionis a method for improving, maintaining, restoring or repairing vision,the method comprising the step of placing in the vitreous of an eye abiodegradable intraocular implant comprising a brimonidine associatedwith a biodegradable polymer, thereby improving, maintaining, restoringor repairing vision.

An embodiment of our invention is a biodegradable intraocular implantcomprising an alpha-2 adrenergic receptor agonist and a biodegradablepolymer, wherein the biodegradable polymer comprises an ester end-cappedbiodegradable polymer and an acid end-capped biodegradable polymer. Theimplant can comprise from about 10% to about 91% ester end-cappedbiodegradable polymer, from about 5 wt % to about 40 wt % acidend-capped biodegradable polymer, and from about 4 wt % to about 50 wt %alpha-2 adrenergic receptor agonist. Preferably, the implant cancomprise from about 45% to about 80% ester end-capped biodegradablepolymer, from about 10 wt % to about 40 wt % acid end-cappedbiodegradable polymer, and about 10 wt % to about 15 wt % alpha-2adrenergic receptor agonist. More preferably, the implant can compriseabout 88 wt % ester end-capped biodegradable polymer, about 10 wt % acidend-capped biodegradable polymer, and about 12 wt % alpha-2 adrenergicreceptor agonist. Most preferably, the implant can comprise from about53 wt % to about 73% ester end-capped biodegradable polymer, from about15 wt % to about 35 wt % acid end-capped biodegradable polymer, and fromabout 9 wt % to about 12 wt % alpha-2 adrenergic receptor agonist.

The biodegradable polymer of the implant can comprise more than oneester end-capped biodegradable polymer. Alternately, the biodegradablepolymer of the implant can comprise more than one acid end-cappedbiodegradable polymer. The implant can have no or a nominal lag timeafter ocular implantation or insertion of the implant before release ofa therapeutically effective amount of the alpha-2 adrenergic receptoragonist from the implant occurs. The implant comprise greater than orequal to 4 weight percent (wt %) of a biologically active alpha-2adrenergic receptor agonist and the implant preferably does not includeany pore forming additives, release rate modulators or release ratemodifiers. The implant can exhibit a sustained release of the alpha-2adrenergic receptor agonist from the biodegradable polymeric matrix overa period of at least 115 days. Additionally, the implant can exhibit asubstantially linear release of the alpha-2 adrenergic receptor agonistfrom the biodegradable polymeric matrix of the implant over a period oftime from about 20 days to about 50 days.

A preferred embodiment of a biodegradable intraocular implant within thescope of our invention can comprise an alpha-2 adrenergic receptoragonist, and a biodegradable polymer, wherein the biodegradable polymercomprises an ester end-capped biodegradable polymer and an acidend-capped biodegradable polymer, wherein the implant comprises fromabout 40% to about 91% of at least two different ester end-cappedbiodegradable polymers, from about 5 wt % to about 40 wt % acidend-capped biodegradable polymer, and from about 4 wt % to about 20 wt %alpha-2 adrenergic receptor agonist.

Our invention also includes a process for making a biodegradableintraocular implant by mixing an alpha-2 adrenergic receptor agonist anda biodegradable polymer, wherein the biodegradable polymer comprises anester end-capped biodegradable polymer and an acid end-cappedbiodegradable polymer; heating the mixture, and; extruding the heatedmixture, to thereby make a biodegradable intraocular implant.

An implant within the scope of our invention can be an extruded filamentwith a diameter of about 0.5 mm, a length of about 6 mm and a weight ofabout 1 mg. The alpha-2 adrenergic receptor agonist can be homogenouslydistributed throughout the implant.

Our implants can be used to treat ocular conditions by intraocularadministration of a biodegradable intraocular implant comprising analpha-2 adrenergic receptor agonist and a biodegradable polymer, whereinthe biodegradable polymer comprises an ester end-capped biodegradablepolymer and an acid end-capped biodegradable polymer. The alpha-2adrenergic receptor agonist can be selected from the group consisting ofbrimonidine, salts thereof, and mixtures thereof.

In another embodiment of our invention a biodegradable intraocularimplant can comprise a plurality of forms of an alpha-2 adrenergicreceptor agonist and a biodegradable polymer. The alpha-2 adrenergicreceptor agonist can be a brimonidine and the brimonidine can be presentin two forms in the implant. The two forms of brimonidine present in theimplant can be brimonidine free base and brimonidine tartrate. Such andimplant can comprises from about 50 wt % to about 70% ester end-cappedbiodegradable polymer, from about 1 wt % to about 49 wt % brimonidinefree base and from about 1 wt % to about 49 wt % brimonidine tartrate.Alternately, the implant can comprises from about 50 wt % to about 60%ester end-capped biodegradable polymer, from about 1 wt % to about 49 wt% brimonidine free base and from about 1 wt % to about 49 wt %brimonidine tartrate. More preferably, the implant can comprise fromabout 50 wt % to about 70% ester end-capped biodegradable polymer, fromabout 10 wt % to about 30 wt % brimonidine free base and from about 10wt % to about 30 wt % brimonidine tartrate. In most preferred embodimentthe implant can comprise from about 55 wt % to about 65% esterend-capped biodegradable polymer, from about 15 wt % to about 20 wt %brimonidine free base and from about 15 wt % to about 20 wt %brimonidine tartrate, for example the implant can comprise about 65 wt %ester end-capped biodegradable polymer, about 18 wt % brimonidine freebase and about 18 wt % brimonidine tartrate. The implant of claim 21,wherein the biodegradable polymer comprises more than one esterend-capped biodegradable polymer. And the implant can have no burstrelease and no or a nominal lag time after ocular implantation orinsertion of the implant before release of a therapeutically effectiveamount of the alpha-2 adrenergic receptor agonist from the implantoccurs. Additionally, the implant can exhibit a sustained release of thealpha-2 adrenergic receptor agonist from the biodegradable polymericmatrix over a period of at least 60 days. Furthermore, the implant canexhibits a substantially linear release of the alpha-2 adrenergicreceptor agonist from the biodegradable polymeric matrix of the implantover a period of time from about 20 days to about 50 days.

A preferred embodiment of our invention can comprise a brimonidine freebase; a brimonidine tartrate, and an ester end-capped biodegradablepolymer, wherein the implant comprises from about 50 wt % to about 70%of the ester end-capped biodegradable polymer, from about 1 wt % toabout 49 wt % of the brimonidine free base and from about 1 wt % toabout 49 wt % of the brimonidine tartrate.

Our invention encompasses a process for making a biodegradableintraocular implant comprising (a) mixing a plurality of forms ofalpha-2 adrenergic receptor agonist and a biodegradable polymer; (b)heating the mixture, and; (c) extruding the heated mixture, to therebymake a biodegradable intraocular implant. The implant can be extruded asa filament with a diameter of about 0.5 mm, a length of about 6 mm and aweight of about 1 mg. The implant can also be made by a directcompression or solvent extraction method. The shape of the implant canalso be as a tablet, pellet or rod.

Finally, our invention encompasses a method of treating a symptom ofglaucoma by placing a biodegradable intraocular implant comprising analpha-2 adrenergic receptor agonist associated with a biodegradablepolymer into the vitreous of an eye, thereby treating a symptom of theglaucoma. The symptom of the glaucoma can be reduced for at least about35 days after intravitreal placement of the implant. The symptom of theglaucoma treated can be an elevated intraocular pressure.

Additional aspects and advantages of the present invention are set forthin the following description and claims, particularly when considered inconjunction with the accompanying drawings.

DRAWINGS

FIG. 1 is a graph showing in vitro cumulative total release ofbrimonidine free base (“BFB”) (y axis) over time in days (X axis) fromthree different polymeric implants made according to the method ofExample 1. The legend in Figure gives for each of the three implants theseven digit, hyphenated formulation number followed by the weightpercent of BFB in the implant (i.e. “35-API” means 35 wt % BFB), andthen the weight percents of each of the three polymers used to make eachof the three implants shown.

FIG. 2 is a graph showing in vitro cumulative total release of two BFBplus BT polymeric implant formulations compared to a BFB only polymericimplant, the axes and legend being formatted as in FIG. 1.

FIG. 3a is a drawing of a bar shaped implant and FIG. 3b is a drawing ofa disc shaped implant, showing exemplary implant dimensions, asexplained in Example 3.

FIG. 4 is a graph showing in vitro cumulative total release from threeBFB bar shaped implants, as set forth in Example 3.

FIG. 5 is a graph showing in vitro cumulative total release from a BFBdisc shaped implant, as set forth in Example 3.

FIG. 6 is a graph showing change of IOP over a 63 day period frombaseline IOP at day zero in rabbits that had received sub-tenonadministration of six 400 ug BT bars (2400 μg brimonidine tartrate), asset forth in Example 3.

DESCRIPTION

Our invention is based on the discovery of novel formulations andconfigurations of one or more forms of an alpha-2-selective adrenergicreceptor agonist therapeutic agent and a biodegradable polymer whichonce heat extruded, or made by injection molding, form implants suitablefor intraocular administration to treat ocular diseases and conditions.Embodiments of our invention have substantially linear therapeutic agentrelease characteristics and/or high I (greater than 50 wt %) drug loadin the implant.

The implants comprise a pharmaceutically acceptable polymericcomposition and are formulated to release one or more pharmaceuticallyactive agents, such as alpha-2 adrenergic receptor agonists, over anextended period of time. The implants are effective to provide atherapeutically effective dosage of the agent or agents directly to aregion of the eye to treat or prevent one or more undesirable ocularconditions. Thus, with a single administration, therapeutic agents willbe made available at the site where they are needed and will bemaintained for an extended period of time, rather than subjecting thepatient to repeated injections or, in the case of self-administereddrops, ineffective treatment with only limited bursts of exposure to theactive agent or agents.

An intraocular implant in accordance with the disclosure hereincomprises a therapeutic component and a drug release sustainingcomponent associated with the therapeutic component. In accordance withthe present invention, the therapeutic component comprises, consistsessentially of, or consists of, an alpha-2 adrenergic receptor agonist.The drug release sustaining component is associated with the therapeuticcomponent to sustain release of a therapeutically effective amount ofthe alpha-2 adrenergic receptor agonist into an eye in which the implantis placed. The therapeutic amount of the alpha-2 adrenergic receptoragonist is released into the eye for a period of time greater than aboutone week after the implant is placed in the eye.

Intraocular implants have been developed which can release drug loadsover various' time periods. These implants, which when inserted into aneye, such as the vitreous of an eye, provide therapeutic levels of analpha-2 adrenergic receptor agonist for extended periods of time (e.g.,for about 1 week or more). The implants disclosed are effective intreating ocular conditions, such as posterior ocular conditions.

In one embodiment of the present invention, an intraocular implantcomprises a biodegradable polymer matrix. The biodegradable polymermatrix is one type of a drug release sustaining component. Thebiodegradable polymer matrix is effective in forming a biodegradableintraocular implant. The biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with the biodegradablepolymer matrix. The matrix degrades at a rate effective to sustainrelease of an amount of the alpha-2 adrenergic receptor agonist for atime greater than about one week from the time in which the implant isplaced in ocular region or ocular site, such as the vitreous of an eye.

The alpha-2 adrenergic receptor agonist of the implant is typically anagent that selectively activates alpha-2 adrenergic receptors relativeto alpha-1 adrenergic receptors. In certain implants, the alpha-2adrenergic receptor agonist selectively activates a subtype of thealpha-2 adrenergic receptors. For example, the agonist may selectivelyactivate one or more of the alpha-2a, the alpha-2b, or the alpha-2creceptors, under certain conditions, such as physiological conditions.Under other conditions, the agonist of the implant may not be selectivefor alpha-2 adrenergic receptor subtypes. The agonist may activate thereceptors by binding to the receptors, or by any other mechanism.

In certain implants, the alpha-2 adrenergic receptor agonist is aquinoxaline derivative. The quinoxaline derivatives useful in thepresent implants are those quinoxaline derivatives having the formula,

pharmaceutically acceptable acid addition salts thereof, and mixturesthereof. R₁ and R₂ each is independently selected from the groupconsisting of H, alkyl radicals containing 1 to 4 carbon atoms andalkoxy radicals containing 1 to 4 carbon atoms. R₂ is preferably amethyl radical. The 2-imidazolin-2-ylamino group may be in any of the5-, 6-, 7- and 8-positions, preferably in the 6-position, of thequinoxaline nucleus. R₃, R₄ and R₅ each is located in one of theremaining 5-, 6-, 7- or 8-positions of the quinoxaline nucleus and isindependently selected from the group consisting of Cl, Br, H and alkylradicals containing 1 to 3 carbon atoms. R₃ is preferably in the5-position of the quinoxaline nucleus, and R₄ and R₅ are preferably bothH. In a particularly useful embodiment R₃ is Br.

In at least one implant, R₁ is H and R₂ is selected from alkyl radicalscontaining 1 to 4 carbon atoms. R₃ may advantageously be in the5-position of the quinoxaline nucleus and be selected from H and alkylradicals containing 1 to 3 carbon atoms. All stereoisomers, tautomersand mixtures thereof which comply with the constraints of one or more ofthe presently useful compounds are included within the scope of thepresent invention.

Pharmaceutically acceptable acid addition salts of the compounds of theinvention are those formed from acids which form non-toxic additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

In more specific implants, the quinoxaline derivative has the formula

In additional implants, the alpha-2 adrenergic receptor agonist isprovided as a salt having the formula

The foregoing salt is known as brimonidine tartrate (AGN 190342-F,5-bromo-6-(2-imidazolidinylideneamino)quinoxaline tartrate), and ispublicly available from Allergan, Inc. under the tradename Alphagan-P®.Brimonidine, an organic base, is publicly available as eitherbrimonidine tartrate salt or as brimonidine freebase. The tartrate saltis more soluble than the freebase in various aqueous media. Since boththe tartrate salt and the freebase are chemically stable and havemelting points higher than 200° C., both forms are suitable in formingthe present implants.

Thus, the implant may comprise a therapeutic component which comprises,consists essentially of, or consists of a brimonidine salt, such asbrimonidine tartrate, a brimonidine free base, or mixtures thereof.

The alpha-2 adrenergic receptor agonist may be in a particulate orpowder form and entrapped by the biodegradable polymer matrix. Usually,alpha-2 adrenergic receptor agonist particles will have an effectiveaverage size less than about 3000 nanometers. In certain implants, theparticles may have an effective average particle size about an order ofmagnitude smaller than 3000 nanometers. For example, the particles mayhave an effective average particle size of less than about 500nanometers. In additional implants, the particles may have an effectiveaverage particle size of less than about 400 nanometers, and in stillfurther embodiments, a size less than about 200 nanometers.

The alpha-2 adrenergic receptor agonist of the implant is preferablyfrom about 10% to 90% by weight of the implant. More preferably, thealpha-2 adrenergic receptor agonist is from about 20% to about 80% byweight of the implant. In a preferred embodiment, the alpha-2 adrenergicreceptor agonist comprises about 20% by weight of the implant (e.g.,15%-25%). In another embodiment, the alpha-2 adrenergic receptor agonistcomprises about 50% by weight of the implant.

Suitable polymeric materials or compositions for use in the implantinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably are atleast partially and more preferably substantially completelybiodegradable or bioerodible.

Examples of useful polymeric materials include, without limitation, suchmaterials derived from and/or including organic esters and organicethers, which when degraded result in physiologically acceptabledegradation products, including the monomers. Also, polymeric materialsderived from and/or including, anhydrides, amides, orthoesters and thelike, by themselves or in combination with other monomers, may also finduse. The polymeric materials may be addition or condensation polymers,advantageously condensation polymers. The polymeric materials may becross-linked or non-cross-linked, for example not more than lightlycross-linked, such as less than about 5%, or less than about 1% of thepolymeric material being cross-linked. For the most part, besides carbonand hydrogen, the polymers will include at least one of oxygen andnitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g.hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylicacid ester, and the like. The nitrogen may be present as amide, cyanoand amino. The polymers set forth in Heller, Biodegradable Polymers inControlled Drug Delivery, In: CRC Critical Reviews in Therapeutic DrugCarrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90,which describes encapsulation for controlled drug delivery, may find usein the present implants.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyvinylalcohol, polyesters, polyethers and combinations thereof which arebiocompatible and may be biodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Equally important to controlling the biodegradation of the polymer andhence the extended release profile of the implant is the relativeaverage molecular weight of the polymeric composition employed in theimplant. Different molecular weights of the same or different polymericcompositions may be included in the implant to modulate the releaseprofile. In certain implants, the relative average molecular weight ofthe polymer will range from about 9 to about 64 kD, usually from about10 to about 54 kD, and more usually from about 12 to about 45 kD.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation is controlled by the ratio of glycolicacid to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic acid and lactic acid. Homopolymers, orcopolymers having ratios other than equal, are more resistant todegradation. The ratio of glycolic acid to lactic acid will also affectthe brittleness of the implant, where a more flexible implant isdesirable for larger geometries. The % of polylactic acid in thepolylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some implants,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the intraocular implant may comprisea mixture of two or more biodegradable polymers. For example, theimplant may comprise a mixture of a first biodegradable polymer and adifferent second biodegradable polymer. One or more of the biodegradablepolymers may have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or combination of both. As discussed herein, thematrix of the intraocular implant may release drug at a rate effectiveto sustain release of an amount of the alpha-2 adrenergic receptoragonist for more than one week after implantation into an eye. Incertain implants, therapeutic amounts of the alpha-2 adrenergic receptoragonist are released for no more than about 30-35 days afterimplantation. For example, an implant may comprise brimonidine tartrate,and the matrix of the implant degrades at a rate effective to sustainrelease of a therapeutically effective amount of brimonidine tartratefor about one month after being placed in an eye. As another example,the implant may comprise brimonidine tartrate, and the matrix releasesdrug at a rate effective to sustain release of a therapeuticallyeffective amount of brimonidine tartrate for more than forty days, suchas for about six months.

One example of the biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with a biodegradablepolymer matrix, which comprises a mixture of different biodegradablepolymers. At least one of the biodegradable polymers can be polylactidehaving a molecular weight from about 40 to about 80 kD. A secondbiodegradable polymer can be a polylactide having a molecular weight offrom about 10 to 20 kD. Such a mixture is effective in sustainingrelease of a therapeutically effective amount of the alpha-2 adrenergicreceptor agonist for a time period greater than about one month from thetime the implant is placed in an eye.

Another example of a biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with a biodegradablepolymer matrix, which comprises a mixture of different biodegradablepolymers, each biodegradable polymer having an inherent viscosity fromabout 0.16 dl/g to about 1.0 dl/g. For example, one of the biodegradablepolymers may have an inherent viscosity of about 0.3 dl/g. A secondbiodegradable polymer may have an inherent viscosity of about 1.0 dl/g.The inherent viscosities identified above may be determined in 0.1%chloroform at 25° C.

One particular implant comprises brimonidine tartrate associated with acombination of two different polylactide polymers. The brimonidinetartrate can present at up to about 60% by weight of the implant. Onepolylactide polymer can have a molecular weight of about 14 kD and aninherent viscosity of about 0.3 dl/g, and the other polylactide polymercan have a molecular weight of about 63.3 kD and an inherent viscosityof about 1.0 dl/g. The two polylactide polymers can be present in theimplant in a 1:1 ratio. Such an implant provides for release of thebrimonidine for more than two months in vitro, as described herein. Theimplant is provided in the form of a rod, bar or disc or a filamentproduced by an extrusion or injection molding process.

The release of the alpha-2 adrenergic receptor agonist from theintraocular implant comprising a biodegradable polymer matrix mayinclude an initial burst of release followed by a gradual increase inthe amount of the alpha-2 adrenergic receptor agonist released, or therelease may include an initial delay in release of the alpha-2adrenergic receptor agonist followed by an increase in release. When theimplant is substantially completely degraded, the percent of the alpha-2adrenergic receptor agonist that has been released is about one hundred.Compared to existing implants, the implants disclosed herein do notcompletely release, or release about 100% of the alpha-2 adrenergicreceptor agonist, until after about one week of being placed in an eye.

It may be desirable to provide a relatively constant rate of release ofthe alpha-2 adrenergic receptor agonist from the implant over the lifeof the implant. For example, it may be desirable for the alpha-2adrenergic receptor agonist to be released in amounts from about 0.01 μgto about 2 μg per day for the life of the implant. However, the releaserate may change to either increase or decrease depending on theformulation of the biodegradable polymer matrix. In addition, therelease profile of the alpha-2 adrenergic receptor agonist may includeone or more linear portions and/or one or more non-linear portions.Preferably, the release rate is greater than zero once the implant hasbegun to degrade or erode.

The implants may be monolithic, i.e. having the active agent or agentshomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix or as a core-shell type of implant. Due to ease of manufacture,monolithic implants are usually preferred over encapsulated forms.However, the greater control afforded by the encapsulated,reservoir-type implant may be of benefit in some circumstances, wherethe therapeutic level of the drug falls within a narrow window. Inaddition, the therapeutic component, including the alpha-2 adrenergicreceptor agonist, may be distributed in a non-homogenous pattern in thematrix. For example, the implant may include a portion that has agreater concentration of the alpha-2 adrenergic receptor agonistrelative to a second portion of the implant.

The intraocular implants disclosed herein may have a size of betweenabout 5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. For non-humanindividuals, the dimensions and total weight of the implant(s) may belarger or smaller, depending on the type of individual. For example,humans have a vitreous volume of approximately 3.8 ml, compared withapproximately 30 ml for horses, and approximately 60-100 ml forelephants. An implant sized for use in a human may be scaled up or downaccordingly for other animals, for example, about 8 times larger for animplant for a horse, or about, for example, 26 times larger for animplant for an elephant.

Thus, implants can be prepared where the center may be of one materialand the surface may have one or more layers of the same or a differentcomposition, where the layers may be cross-linked, or of a differentmolecular weight, different density or porosity, or the like. Forexample, where it is desirable to quickly release an initial bolus ofdrug, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The implants may be of any geometry including fibers, sheets, films,microspheres, spheres, circular discs, plaques and the like. The upperlimit for the implant size will be determined by factors such astoleration for the implant, size limitations on insertion, ease ofhandling, etc. Where sheets or films are employed, the sheets or filmswill be in the range of at least about 0.5 mm×0.5 mm, usually about 3-10mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling.Where fibers are employed, the fiber diameter will generally be in therange of about 0.05 to 3 mm and the fiber length will generally be inthe range of about 0.5-10 mm. Spheres may be in the range of 0.5 μm to 4mm in diameter, with comparable volumes for other shaped particles.

The size and form of the implant can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of the implant are chosento suit the site of implantation.

The proportions of alpha-2 adrenergic receptor agonist, polymer, and anyother modifiers may be empirically determined by formulating severalimplants with varying proportions. A USP approved method for dissolutionor release test can be used to measure the rate of release (USP 23; NF18 (1995) pp. 1790-1798). For example, using the infinite sink method, aweighed sample of the implant is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration is after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly tomaintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

In addition to the alpha-2 adrenergic receptor agonist or alpha-2adrenergic receptor agonists included in the intraocular implantsdisclosed herein, the intraocular implants may also include one or moreadditional ophthalmically acceptable therapeutic agents. For example,the implant may include one or more antihistamines, one or moreantibiotics, one or more beta blockers, one or more steroids, one ormore antineoplastic agents, one or more immunosuppressive agents, one ormore antiviral agents, one or more antioxidant agents, and mixturesthereof.

Pharmacologic or therapeutic agents which may find use in the presentsystems, include, without limitation, those disclosed in U.S. Pat. No.4,474,451, columns 4-6 and U.S. Pat. No. 4,327,725, columns 7-8.

Examples of antihistamines include, and are not limited to, loratadine,hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimeprazinedoxylamine, pheniramine, pyrilamine, chlorcyclizine, thonzylamine, andderivatives thereof.

Examples of antibiotics include without limitation, cefazolin,cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan,cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin,cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin,cyclacillin, ampicillin, penicillin G, penicillin V potassium,piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin,azlocillin, carbenicillin, methicillin, nafcillin, erythromycin,tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol,ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin,lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate,colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim, andderivatives thereof.

Examples of beta blockers include acebutolol, atenolol, labetalol,metoprolol, propranolol, timolol, and derivatives thereof.

Examples of steroids include corticosteroids, such as cortisone,prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol,fluazacort, hydrocortisone, prednisone, betamethasone, prednisone,methylprednisolone, triamcinolone hexacetonide, paramethasone acetate,diflorasone, fluocinonide, fluocinolone, triamcinolone, derivativesthereof, and mixtures thereof.

Examples of antineoplastic agents include adriamycin, cyclophosphamide,actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin,mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU),methyl-CCNU, cisplatin, etoposide, interferons, camptothecin andderivatives thereof, phenesterine, taxol and derivatives thereof,taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen,etoposide, piposulfan, cyclophosphamide, and flutamide, and derivativesthereof.

Examples of immunosuppressive agents include cyclosporine, azathioprine,tacrolimus, and derivatives thereof.

Examples of antiviral agents include interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, valacyclovir,dideoxycytidine, phosphonoformic acid, ganciclovir, and derivativesthereof.

Examples of antioxidant agents include ascorbate, alpha-tocopherol,mannitol, reduced glutathione, various carotenoids, cysteine, uric acid,taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin,cryptoxanthin, astaxanthin, lycopene, N-acetyl-cysteine, carnosine,gamma-glutamylcysteine, quercetin, lactoferrin, dihydrolipoic acid,citrate, Ginkgo Biloba extract, tea catechins, bilberry extract,vitamins E or esters of vitamin E, retinyl palmitate, and derivativesthereof.

Other therapeutic agents include squalamine, carbonic anhydraseinhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics,antifungals, and derivatives thereof.

The amount of active agent or agents employed in the implant,individually or in combination, will vary widely depending on theeffective dosage required and the desired rate of release from theimplant. Usually the agent will be at least about 1, more usually atleast about 10 weight percent of the implant, and usually not more thanabout 80, more usually not more than about 40 weight percent of theimplant.

In addition to the therapeutic component, the intraocular implantsdisclosed herein may include effective amounts of buffering agents,preservatives and the like. Suitable water soluble buffering agentsinclude, without limitation, alkali and alkaline earth carbonates,phosphates, bicarbonates, citrates, borates, acetates, succinates andthe like, such as sodium phosphate, citrate, borate, acetate,bicarbonate, carbonate and the like. These agents advantageously presentin amounts sufficient to maintain a pH of the system of between about 2to about 9 and more preferably about 4 to about 8. As such the bufferingagent may be as much as about 5% by weight of the total implant.Suitable water soluble preservatives include sodium bisulfite, sodiumbisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricborate, phenylmercuric nitrate, parabens, methylparaben, polyvinylalcohol, benzyl alcohol, phenylethanol and the like and mixturesthereof. These agents may be present in amounts from 0.001 to about 5%by weight and preferably 0.01 to about 2% by weight. In at least one ofthe present implants, a purite preservative is provided in the implant,such as when the alpha-2 adrenergic receptor agonist is brimonidine.Thus, these implants may contain a therapeutically effective amount ofAlphagan-P®.

In some situations mixtures of implants may be utilized employing thesame or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried.

Additionally, release modulators such as those described in U. S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of the alpha-2adrenergic receptor agonist in the absence of modulator. Electrolytessuch as sodium chloride and potassium chloride may also be included inthe implant. Where the buffering agent or enhancer is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug bioerosion. Similarly,a hydrophobic buffering agent or enhancer dissolve more slowly, slowingthe exposure of drug particles, and thereby slowing the rate of drugbioerosion.

In certain implants, an implant (or a plurality of up to six implants)comprising brimonidine or brimonidine tartrate and a biodegradablepolymer matrix is able to release or deliver an amount of brimonidinebetween about 0.1 mg to about 2.4 mg for about 3-6 months afterimplantation into the eye. The implant may be configured as a rod, bar,disc or wafer. A rod-shaped implant may be derived from filamentsextruded from a 720 μm nozzle and cut into 1 mg size. A wafer-shapedimplant may be a circular disc having a diameter of about 2.5 mm, athickness of about 0.127 mm, and a weight of about 1 mg.

The proposed 3-month release formulations may be sterile, andbioerodible in the form of a rod, a wafer or a microsphere containingbrimonidine tartrate within a PLA matrix or POE matrix. The implants aredesigned to delay the clearance of the drug and reduce the need forrepeated implantation over 3-month period, thereby lowering the risk ofcomplications.

Various techniques may be employed to produce the implants describedherein. Useful techniques include, but are not necessarily limited to,solvent evaporation methods, phase separation methods, interfacialmethods, molding methods, injection molding methods, extrusion methods,co-extrusion methods, carver press method, die cutting methods, heatcompression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the implants, and typicallyyield implants with faster release rates than extrusion methods.Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

The implants of the present invention may be inserted into the eye, forexample the vitreous chamber of the eye, by a variety of methods,including placement by forceps or by trocar following making a 2-3 mmincision in the sclera. One example of a device that may be used toinsert the implants into an eye is disclosed in U.S. Patent PublicationNo. 2004/0054374. The method of placement may influence the therapeuticcomponent or drug release kinetics. For example, delivering the implantwith a trocar may result in placement of the implant deeper within thevitreous than placement by forceps, which may result in the implantbeing closer to the edge of the vitreous. The location of the implantmay influence the concentration gradients of therapeutic component ordrug surrounding the element, and thus influence the release rates(e.g., an element placed closer to the edge of the vitreous may resultin a slower release rate).

The present implants are configured to release an amount of alpha-2adrenergic receptor agonist in an eye for a period of time to minimizean ocular vascular occlusion, such as a retinal vascular occlusion.Retinal vascular occlusion may result from a variety of diseases such asretinal arterial occlusive disease, central retinal vein occlusion,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, hemi-retinal vein occlusion, central retinal arteryocclusion, branch retinal artery occlusion, carotid artery disease(cad), eales disease and vasculopathies associated with diabetes. Byimplanting the alpha-2 adrenergic receptor agonist-containing implantsinto the vitreous of an eye, it is believed that the agonist iseffective to reduce occlusion within blood vessels located in the eye.

In addition, the present implants may be configured to release analpha-2 adrenergic receptor agonist in a therapeutically effectiveamount for a period of time effective to treat glaucoma of a patient.

The implants disclosed herein may also be configured to releaseadditional therapeutic agents, as described above, which may beeffective in treating diseases or conditions, such as the following:

Maculopathies/retinal degeneration: macular degeneration, including agerelated macular degeneration (ARMD), such as non-exudative age relatedmacular degeneration and exudative age related macular degeneration,choroidal neovascularization, retinopathy, including diabeticretinopathy, acute and chronic macular neuroretinopathy, central serouschorioretinopathy, and macular edema, including cystoid macular edema,and diabetic macular edema. Uveitis/retinitis/choroiditis: acutemultifocal placoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), uveitis, including intermediate uveitis (pars planitis)and anterior uveitis, multifocal choroiditis, multiple evanescent whitedot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis,serpignous choroiditis, subretinal fibrosis, uveitis syndrome, andVogt-Koyanagi-Harada syndrome. Vascular diseases/exudative diseases:retinal arterial occlusive disease, central retinal vein occlusion,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasia, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, Eales disease.Traumatic/surgical: sympathetic ophthalmia, uveitic retinal disease,retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusionduring surgery, radiation retinopathy, bone marrow transplantretinopathy. Proliferative disorders: proliferative vitreal retinopathyand epiretinal membranes, proliferative diabetic retinopathy. Infectiousdisorders: ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associatedwith HIV infection, uveitic disease associated with HIV Infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis. Genetic disorders:retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Bests disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, pseudoxanthoma elasticum. Retinal tears/holes:retinal detachment, macular hole, giant retinal tear. Tumors: retinaldisease associated with tumors, congenital hypertrophy of the RPE,posterior uveal melanoma, choroidal hemangioma, choroidal osteoma,choroidal metastasis, combined hamartoma of the retina and retinalpigmented epithelium, retinoblastoma, vasoproliferative tumors of theocular fundus, retinal astrocytoma, intraocular lymphoid tumors.Miscellaneous: punctate inner choroidopathy, acute posterior multifocalplacoid pigment epitheliopathy, myopic retinal degeneration, acuteretinal pigment epithelitis and the like.

In one embodiment, an implant, such as the implants disclosed herein, isadministered to a posterior segment of an eye of a human or animalpatient, and preferably, a living human or animal. In at least oneembodiment, an implant is administered without accessing the subretinalspace of the eye. For example, a method of treating a patient mayinclude placing the implant directly into the posterior chamber of theeye. In other embodiments, a method of treating a patient may compriseadministering an implant to the patient by at least one of intravitrealinjection, subconjunctival injection, sub-tenon injections, retrobulbarinjection, and suprachoroidal injection.

In at least one embodiment, a method of reducing retinal vascularocclusion in a patient comprises administering one or more implantscontaining one or more alpha-2 adrenergic receptor agonists, asdisclosed herein to a patient by at least one of intravitreal injection,subconjunctival injection, sub-tenon injection, retrobulbar injection,and suprachoroidal injection. A syringe apparatus including anappropriately sized needle, for example, a 27 gauge needle or a 30 gaugeneedle, can be effectively used to inject the composition with theposterior segment of an eye of a human or animal. Repeat injections areoften not necessary due to the extended release of the alpha-2adrenergic receptor agonists from the implants.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container comprisingan extended release implant comprising a therapeutic component includingan alpha-2 adrenergic receptor agonist, such as brimonidine free base orbrimonidine tartrate (e.g., Alphagan-P), and a drug release sustainingcomponent; and b) instructions for use. Instructions may include stepsof how to handle the implants, how to insert the implants into an ocularregion, and what to expect from using the implants.

EXAMPLES

The following examples illustrate embodiments of our invention. Wedeveloped the formulations set forth in the Examples below withconsiderably difficultly. Thus, over a hundred formulations were testedbefore arriving at the specific useful formulation set forth in theExamples below. We determined that with drug (i.e. brimonidine) loadsgreater than about 35 weight %, high burst and subsequent poor drugrelease profile ensures. Thus, we determined that many formulations ofbrimonidine free base (BFB) presented in vitro a lag release periodwhile many brimonidine tartrate (BT) formulations showed an initialburst release. Additionally, we determined that many 50:50 (BT: BFB)formulations displayed burst and a late-stage poor (very slow or minimalrate of) drug release.

However, we persevered and discovered that specific BT, BFB, and polymer(PLA and PLGA) combinations achieved desirable release profiles, asshown in FIG. 1. We determined that addition of low molecular weightacid end-capped poly (D,L-lactide-co-glycolide) polymer (RG502H) and alower proportion of BT were important to obtaining the desired releasecharacteristics and that presence in the formulations of only the twoester end-capped poly (D,L-lactide) polymer (R203s and R208) did notshow the desired release profile. Hence, a particular hydrophilic tohydrophobic polymer balance was important in order to achieve thecorrect release profile.

Previously it was thought that use of low molecular weight (molecularweight less than about 20,000 Daltons and preferably less than all15,000 Daltons) hydrophilic polymer would cause the extrudeddrug-implant made to have a significantly initial burst release.Contrarily we determined, for example, that use of particular amounts,ratios and proportions of the low molecular weight polymers: esterend-capped poly (D,L-lactide) in combination with two ester end-cappedpoly (D,L-lactide) polymers (i.e. R203s and R208) resulted in adesirable linear and non-burst release profile.

Example 1 High-Load Brimonidine Implant With Improved Release Profile

As previously set forth it is known that topical application of thealpha-2 adrenergic receptor agonist brimonidine is effective whentopically administered to treat open-angle glaucoma and ocularhypertension. Brimonidine also has neuroprotective and visual acuityenhancing properties when given intravitreally. We determined that asustained release polymer implant can effectively deliver a therapeuticdose of brimonidine over an extended period of time in the Tenon'scapsule (i.e. into the sub-tenon space) and/or into the vitreous fortreating, respectively, an anterior or a posterior ocular condition. Itis highly advantageous for an implant to carry (i.e. by loaded with) asmuch active drug as possible so as to increase (upon regular, periodrelease of the therapeutic agent from the administered implant) theduration of therapeutic drug dosing. In this Example, we surprisinglydetermined that use of brimonidine free base (BFB) instead ofbrimonidine tartrate (BT) enables an implant constituted of particularbioerodible polymers to carry 51% more moles of BFB as opposed to BT foran equal weight implant comprising the same polymers and made by thesame process. BFB however is not as water soluble as is BT (the tartratesalt of brimonidine) so there can be a substantial lag time in the BFBrelease profile upon administration of the implant. Additionally,implants with higher loads of BT often show a “burst” release (ascompared to BFB) because of BT's high solubility. Hence, we additionallydeveloped new formulations with particular polymers which, as well aspermitting significantly higher BFB drug loads (as compared to the wt %drug load possible with BT as the drug) also exhibit substantiallylinear release profiles of the brimonidine free-base from the particularpolymers new formulation sustained release polymer implants wediscovered from the infinite combinations of possible polymers.

Specifically, we developed a high-load brimonidine free-base containingsustained release polymer implant with an improved release profile thatdoes not show an initial “burst” or a “lag” period and our newformulation contains brimonidine free base (BFB) dispersed in abiodegradable polymer matrix. In this Example, the polymer matrixconsisted of two poly (D,L-lactide) (PLA) polymers and one poly(D,L-lactide-co-glycolide) (PLGA) polymer. Brimonidine free base ispoorly water soluble and makes the implant more hydrophobic so typicallyupon implantation initial water permeation is delayed and consequentlyso is the release of BFB and a “lag” is observed. Surprisingly, thehigh-load implant we developed contains as much as 60 weight % BFB andyet shows a nearly linear release profile without a burst or lag period.

As an embodiment within the scope of our invention we made heat extrudedimplants (formulation R-2007-8933-028) containing 50 wt % (high load)BFB, 20 wt % R203S (a PLA polymer), 20 wt % R208 (also a PLA polymer),and 10 wt % RG502H (a PLGA polymer). Another embodiment of our inventionwas a heat extruded implant (formulation R-2007-8933-060) comprising 60wt % (very high load) BFB, 16 wt % R203S , 16 wt % R208, and 8 wt %RG502H. Polymers were used as received from Boehringer Ingelheim(Resomer®). Brimonidine free base and brimonidine tartrate were obtainedfrom Ash Stevens, Inc. (Riverview, Mich.).

The polymer implants in this experiment were made by melt (heat)extrusion using a twin-screw microcompounder/extruder (such as that madeby DSM), but they can also be made by direct compression or by solventcasting. The implants made were bar-shaped (with average dimensions of1.0 mm×0.5 mm), but they can be made into any geometric shape bychanging the extrusion or compression die.

The polymers selected and BFB were combined in a stainless steelcontainer containing two 10-mm stainless steel balls and blended in aTurbula mixer for 15 minutes. The container was removed from the mixerand the powder blend was stirred with a spatula. The powder blend wasinspected for homogeneity and the mixing procedure was repeated.

The DSM twin-screw microcompounder/extruder was setup according to themanufacturer's instructions. The output of the extruder was fitted witha laser micrometer and a puller to control the thickness of the extrudedbar. The DSM twin-screw microcompounder/extruder was allowed toequilibrate to the extrusion temperature (between 85° and 110° C.), thenthe powder blend was manually fed into the extrusion screws at a rate of2 grams/minute, which rate maintained a constant load and torque.

The extruded filaments were then cut into two-milligram bars(approximately 3-mm long) and their drug release monitored in phosphatebuffered saline (pH 7.4, 0.01M) by HPLC. The in vitro release dataobtained from sample formulations made in this Example 1 are shown inFIG. 1. Other series of formulations, with 60% loading of BFB, but witha different polymer ratio showed this release rate effect as well.Examples of the formulations made are summarized in Table 1.

TABLE 1 Brimonidine Free Base Containing Formulations Weight %Formulation Brimonidine Resomer Resomer Resomer No Free Base R203S¹R208¹ RG502H² R-2007-8933-027 35 35 20 10 R-2007-8933-028 50 20 20 10R-2007-8933-060 60 16 16 8 ¹Ester end-capped poly (D,L-lactide) polymer²Ester end-capped poly (D,L-lactide-co-glycolide) polymer

This experiment surprisingly showed that high load BFB implants can bemade with substantially linear release rate (i.e. straight line releaseover time) as shown for example over days 5 to 50 for the 60 wt % BFBFIG. 1 implant.

Example 2 Brimonidine Implant With Linear Release Kinetics

Brimonidine tartrate is more water soluble than brimonidine free base soimplants containing BT often show a “burst” release because of theavailability of surface brimonidine tartrate. On the other hand,brimonidine free base is not water soluble and makes the implant morehydrophobic. In this case, initial water permeation is delayed andconsequently so is the release of brimonidine, which is observed as a“lag” in the BFB release profile.

In this experiment we discovered implants formulations with moresubstantially linear release rates than was obtained with the Example 1implants, and as well without significant either burst or lagbrimonidine release observed from the implant. Thus we developed thesenew Example 3 formulations as combinations of brimonidine free base(BFB) and brimonidine tartrate (BT) dispersed in a biodegradable matrixcomprising several different polymers. In this example, the mostpreferred formulation (R-2007-8933-035) consisted of a polymer matrixwhich was a mixture of two different ester end-capped PLAs and one acidend-capped PLA as well as BFB and BT. So in this Example we developedsustained release drug-delivery formulations that is structurally stableand provides zero order (linear) release kinetics without an initialburst effect or lag. The formulations made are summarized in Table 2 andthe release profiles are shown in FIG. 2.

RG502H is (50:50) poly(D,L-lactide-co-glycolide), RG752s is (75:25)poly(D,L-lactide-co-glycolide), R202H is 100% poly(D,L-lactide) withacid end group or terminal acid groups, R203 and R206 are both 100%poly(D,L-lactide). The inherent viscosity of RG502, RG752, R202H, R203,and R206 0.2, 0.2, 0.2, 0.3 and 1.0 dL/g, respectively. The inherentviscosity of both RG502H and RG752s is between 0.16 and 0.24 dl/g. Theinherent viscosity of R203s is between 0.25 and 0.35 dl/g. The averagemolecular weight of RG502, RG752, R202H, R203, and R206 are 11700,11200, 6500, 14000, and 63300 Daltons, respectively.

TABLE 2 BT and BFB Containing Formulations Weight % FormulationBrimonidine Brimonidine Resomer Resomer Resomer Resomer No Free BaseTartrate R203S¹ R208¹ RG502H² R202H³ R-2007-8933-032 25 10 35 20 10 0R-2007-8933-033 40 10 20 20 10 0 R-2007-8933-034 25 10 35 20 0 10R-2007-8933-035 40 10 20 20 0 10 ¹Ester end-capped poly (D,L,-lactide)polymer ²Acid end-capped poly (D,L,-lactide-co-glycolide) polymer ³Acidend-capped poly (D,L,-lactide) polymer

The Example 2 formulations made contained brimonidine free base,brimonidine tartrate, two hydrophobic, ester end-capped poly(D,L-lactide) polymers (PLA), and an acid end-capped poly(D,L-lactide-co-glycolide) polymer (PLGA). One formulation(R-2007-8933-035) contained 40% BFB, 10% BT, 20% R203S (a PLA), 20% R208(a second PLA), and 10% R202H (also a third PLA) and exhibited nearperfect linear release kinetics, the dotted line in FIG. 2 representingperfect linear release. FIG. 2 additionally shows a comparison of theExample 2 new formulation three polymer formulations made with and anExample 1 high load BFB implant. Other formulations we made with thesame BFB:BT ratio but with a different polymer ratio failed to show thesame zero order release kinetics.

The implants were made using the same heat extrusion process set forthin Example 1 and in vivo release data was also obtained by the methodset forth in Example 1.

Example 3 High-Load Extruded Bars and Injection-Molded Discs for OcularSustained Release Polymer Implants

In this experiment we made bar-shaped and disc-shaped sustained releasepolymer implants, which are inserted in vivo below the Tenon's capsuleand above the sclera at a point posterior to the limbus of the eye fortherapeutic purposes (to reduce IOP). We found that release of drug invivo was controlled and maintained for long periods of time with littledrug at sites anatomically distant from the intraocular site ofadministration.

The distinct (bar or disc) shape of the implants made in this Examplemaximized the contact surface area of implant to the episcleral(intrascleral) region, which is desirable for this diffusion-basedimplant system. We also found that having rounded edges on the long axisof the bar-shaped implants reduced the potential for overlyingconjunctival erosions and the potential for implant extrusion from thesite of administration, as compared to rod or filament shaped implantswhich have a cylindrical shape. Advantageously, these low-profile, flat(bar or disc) implants, place the long axis of the implant parallel tothe limbus in the sub-Tenon's space. These implant can also be injected,which is an important advantage over surgically implanted implants. Abar shaped implant (vs rod-shaped) is also less likely to roll with theblinking action and this gives such an implant greater stability andless foreign body sensation for the patient. Lastly, given that the barimplant has two distinct flat sides; one side can be coated with apolymer that may reduce the diffusion of drug towards the conjunctivalside and encourages more drug-release towards the scleral side. Reducingthe drug exposure to the conjunctiva is advantageous because the richsupply of lymphatic vessels in the conjunctiva bilayer is very efficientat clearing drugs from the sub-Tenon's space, and, consequently,reducing the drug exposure to the target tissue (i.e., the ciliary bodyregion).

The disc implant's shape, have a preferred height of less than or equalto 1.0 mm, but preferably less than or equal to 0.5 mm, which can reducethe potential for conjunctival erosions. The disc-shaped implants havethe advantages of holding a large amount of drug and a reduced tendencyto erode from the sub-Tenon's space.

The bar-shaped implants in this study were made by melt extrusion in atwin-screw micro extruder, but they can also be made by directcompression or by solvent casting.

One example of a bar-shaped formulation made by melt extrusion(R-2007-8933-059) contained brimonidine free base (BFB) dispersed in abiodegradable polymer matrix with the in vivo release characteristicsshown in FIG. 4. In this 059 formulation the polymer matrix consisted oftwo poly (D,L-lactide) PLA polymers and one poly(D,L,-lactide-co-glycolide) polymer. Other series of formulations, with60% loading of BFB, but with a different polymer ratio showed thislinear release effect as well. The BFB formulations made are summarizedin Table 3.

TABLE 3 Brimonidine Free Base Containing Formulations Weight %Formulation Brimonidine Resomer Resomer Resomer No Free Base R203S¹R208¹ RG502H² R-2007-8933-027 35 35 20 10 R-2007-8933-059 50 20 20 10R-2007-8933-060 60 16 16 8 ¹Ester end-capped poly (D,L,-lactide) polymer²Acid end-capped poly (D,L,-lactide-co-glycolide) polymer

The combined twin-screw micro extruder and injection molding system wasused to make the disc shaped implants. The melt stream from thetwin-screw micro extruder was directed through the die orifice where itimmediately entered a heated transfer cylinder. As the melt filled thecylinder, the plunger was pushed out of the cylinder. Next the cylinderwas placed in the molder cradle of the injection molding unit. Apneumatic ram pushed the plunger forcing the melt into the mold where itis cooled and solidified. The molded samples were recovered from themold with a compressed air assist if required. The disc-shaped implantsweighed approximately 3.5 milligram and their in vivo drug release wasmonitored in phosphate buffered saline pH 7.4 by HPLC.

FIG. 5 shows that the release profile of disc-shaped formulation made byinjection molding. This formulation (R-2007-8933-064) contained 50% BFB,18% R203S, 18% R208, 8% RG752s, and 6% PEG-3350. Other series offormulations, with similar loading of BFB, but with a different polymerratio show this effect as well. The disc shaped formulations made aresummarized in Table 4.

TABLE 4 Brimonidine Free Base Containing Formulations Weight %Formulation Brimonidine Resomer Resomer Resomer Resomer Resomer PEG NoFree Base R203S¹ R208¹ RG752s² RG502H² R202H³ 3350 R-2007-8933-064 50 1818 8 0 0 6 R-2007-8933-065 50 18 18 0 8 0 6 R-2007-8933-066 50 18 18 0 08 6 ¹Ester end-capped poly (D,L,-lactide) polymer ²Acid end-capped poly(D,L,-lactide-co-glycolide) polymer ³Acid end-capped poly (D,L,-lactide)polymer

Sub-Tenon's Implanted bar-shaped implants show IOP reduction in rabbits.Thus, four NZW rabbits were anesthetized and prepared for eye surgery. Alid speculum was placed and a conjunctival incision was made withWestcott scissors in the superotemporal quadrant. A sub-Tenon's pocketwas made and four brimonidine tartrate bar implants (formulation number:R-2007-8931-008G, 60% drug, 20% R203s, 20% R208) (each containing 600 ugBT) were placed on the episclera. The conjunctiva was re-approximatedusing 9-0 vicryl suture. The eyes demonstrated a sustained IOP reductionover a number of weeks with the sub-Tenon's bar implants. The meanreduction of IOP (measured in % change from baseline) was 25% by 7 days.Thereafter, the IOP reduction ranged from 25 to 42% and returned tobaseline by 8 weeks. The bar implants were well tolerated and theanimals did not exhibit any discomfort. Clinical examination showed nosigns of conjunctival erosion over the implants and no signs ofextrusion of any implant. The percent IOP reduction over time is shownin FIG. 6.

Example 4 Treatment of Glaucoma With an Intraocular Implant ContainingBrimonidine Associated With a Biodegradable Polymer Matrix

A 68 year old female is diagnosed with elevated intraocular pressurelevels, and diagnoses glaucoma. A 2 mg bar shaped implant containing1,200 μg of brimonidine tartrate (formulation 8933-060 of Example 1) isplaced in the vitreous of both of the woman's eyes using a trocar.Alternately, the implant can be administered to the sub tenon space.After about 2 days intraocular pressure has decrease 40-50% frombaseline.

The embodiments of our invention in the Examples above have theadvantages of: (1) providing a sustained release formulation of analpha-2-selective adrenergic receptor agonist, such as brimonidine whichcan be administered (i.e. by intrascleral injection or implantation of asuitable implant) once every one to six months to provide regular dosingof the alpha-2-selective adrenergic receptor agonist therapeutic agentto the eye of a patient in need thereof to thereby treat an ocularcondition such as the elevated intraocular pressure characteristic ofglaucoma; (2) provide a sustained release formulation of analpha-2-selective adrenergic receptor agonist, such as brimonidine,which can be administered (i.e. by intravitreal injection orimplantation of a suitable implant) once every one to six months toprovide regular dosing of the alpha-2-selective adrenergic receptoragonist therapeutic agent to the eye of a patient in need thereof tothereby treat an ocular condition such as neurodegeneration anotherretinal disorder or condition such as macular degeneration, macularedema or other retinopathy, and (3) provide an intraocular, sustainedrelease formulation of an alpha-2 agonist for treating glaucoma whichdoes not have or has reduced side effects of rapid drug wash out, oculardiscomfort, conjunctival hyperemia (eye redness), stinging, pain,decreased tear production and function, decreased tear film stability,superficial punctate keratitis, squamous cell metaplasia, and changes incell morphology.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

We claim:
 1. A method for treating age-related macular degenerationcomprising the step of intraocular injection of a biodegradableintraocular implant comprising: (a) about 50 weight percent brimonidinefree base, and; (b) a biodegradable polymer which is a mixture of: (i)an acid end capped polymer (D,L-lactide) polymer, and (ii) a poly(D,L-lactide-co-glycolide) polymer; and wherein the total weight of thebiodegradable intraocular implant is between 250 μg and 5000 μg.
 2. Theimplant of claim 1, wherein the implant is an extruded rod.
 3. Themethod of claim 2, wherein the macular degeneration is atrophic maculardegeneration.
 4. The method of claim 1, wherein the implant is injectedintravitreally.